The field of the invention is nuclear magnetic resonance imaging methods and systems. More particularly, the invention relates to the imaging of amyloid plaques in subjects with Alzheimer's disease.
When a substance such as human tissue is subjected to a uniform magnetic field (polarizing field B0), the individual magnetic moments of the spins in the tissue attempt to align with this polarizing field, but precess about it in random order at their characteristic Larmor frequency. If the substance, or tissue, is subjected to a magnetic field (excitation field B1) which is in the x-y plane and which is near the Larmor frequency, the net aligned longitudinal magnetization Mz, may be rotated, or “tipped”, into the x-y plane to produce a net transverse magnetization Mt. A signal is emitted by the excited spins after the excitation signal B1 is terminated, this signal may be received and processed to form an image.
When utilizing these signals to produce images, magnetic field gradients (Gx, Gy and Gz) are employed. Typically, the region to be imaged is scanned by a sequence of measurement cycles in which these gradients vary according to the particular localization method being used. The resulting set of received NMR signals are digitized and processed to reconstruct the image using one of many well known reconstruction techniques.
The present invention will be described in detail with reference to a variant of the well known Fourier transform (FT) imaging technique, which is frequently referred to as “spin-warp”. The spin-warp technique is discussed in an article entitled “Spin-Warp NMR Imaging and Applications to Human Whole-Body Imaging” by W. A. Edelstein et al., Physics in Medicine and Biology, Vol. 25, pp. 751-756 (1980). It employs a variable amplitude phase encoding magnetic field gradient pulse prior to the acquisition of NMR spin-echo signals to phase encode spatial information in the direction of this gradient. In a two-dimensional implementation (2DFT), for example, spatial information is encoded in one direction by applying a phase encoding gradient (Gy) along that direction, and then a spin-echo signal is acquired in the presence of a readout magnetic field gradient (Gx) in a direction orthogonal to the phase encoding direction. The readout gradient present during the spin-echo acquisition encodes spatial information in the orthogonal direction. In a typical 2DFT pulse sequence, the magnitude of the phase encoding gradient pulse Gy is incremented in the sequence of views that are acquired during the scan to produce a set of NMR data from which an entire image can be reconstructed.
Alzheimer's disease (AD) is a slowly progressive neurodegenerative disorder with an insidious clinical onset. Above 65 years of age, AD increases in incidence exponentially with age and is therefore poised to become a leading public health problem as the population ages. At this time, no diagnostic biomarker exists. The antemortem diagnosis as well as longitudinal assessment of disease progression are based on clinical and neuropsychometric measures. Due to the anticipated arrival of useful therapeutic interventions for AD, improved methods of diagnosis and measures of disease progression are needed.
Recent evidence in genetics and cell biology have led to general acceptance that the initiating event ultimately leading to clinical AD is disordered metabolism of amyloid in the brain. Amyloid precursor protein (APP) is a normal transmembrane protein found in cells throughout the body. Amyloid β peptide (Aβ) is one of the products of normal metabolic turnover of APP in the brain. Aβ is a major component of extracellular senile (or amyloid) plaques, and, aggregation of extracellular Aβ fragments is thought to be the initiating event in plaque formation. Soluble Aβ polymers are neurotoxic. While plaques themselves may or may not be directly neurotoxic, plaque burden is a measure of the antecedent biochemical events ultimately leading to clinical AD.
The three known types of mutations associated with early onset, familial AD all directly effect amyloid metabolism. Murine models of AD have been created by inserting one or more human mutations into the mouse genome. These transgenic mice display extensive plaque formation, whereas plaques are not found in wild type mice. Amyloid reduction in humans has recently been identified as a major therapeutic objective. Alzheimer's transgenic mice allow controlled study of this phenomenon and enable testing of anti-amyloid interventions that might be useful in humans.
Direct imaging of amyloid in the brain is feasible. Plaque binding scintigraphic probes label plaques in animal and human specimens in vitro, and in vivo in mice. Plaque burden has successfully been visualized with position emission tomography (PET) in living human Alzheimer's patients using the “Pittsburgh” compound. Optical imaging of individual probe labeled plaques has also been demonstrated. Despite this success with other modalities, several groups have pursued imaging of amyloid plaques with MRI. A major motivation for this effort is that, unlike other modalities, MRI theoretically can resolve individual plaques noninvasively. Typical plaques in human AD subjects range from 2 to 200 μm in diameter which is beyond the spatial resolution of PET.
Benvineste, et al. in “Detection of neuritic plaques in Alzheimer's disease by magnetic resonance microscopy,” Proceedings of the National Academy of Sciences of the Untied States of America 1999; 96(24):14079-14084, demonstrated individual plaques on in vitro human tissue slices using MR microscopy. This was accomplished at 7 T at a spatial resolution in the range of 40 μm×40 μm×40 μm (˜6×10−5 mm3). Plaques appeared dark on T2*-weighted images and this was attributed to the known presence of metals, particularly iron, in plaques. However, Poduslo, et al, demonstrated in “Molecular Targeting Of Alzheimer's Amyloid Plaques For Contrast-Enhanced Magnetic Resonance Imaging,” Neurobiology of Disease 2002, 11:315-329, that imaging of plaques in ex vivo transgenic mouse brain specimens at 7 T without administration of an exogenous contrast agent on T2-weighted images could be achieved. Poduslo, et al. also demonstrated enhancement of plaques ex vivo both on T2 and T1-weighted images following IV administration of a specifically designed molecular contrast agent. However, imaging times in these experiments ranged from 13-15 hours which is clearly unsuitable for in vivo imaging.